Author:

Keywords:

Alzheimer Disease, Amyloid beta-Protein Precursor, Animals, COS Cells, Cell Line, Cercopithecus aethiops, Endopeptidases, Gene Expression Regulation, Hela Cells, Humans, Membranes, Mice, Peptide Hydrolases, Protein Processing, Post-Translational, Protein Structure, Tertiary, Research Support, Non-U.S. Gov't, Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Cell Biology, Alzheimer's disease, amyloid precursor protein, regulated intramembrane proteolysis, secretase, APP INTRACELLULAR DOMAIN, GAMMA-SECRETASE, SIGNAL-TRANSDUCTION, ALZHEIMERS-DISEASE, BINDING DOMAIN, PRESENILINS, COMPLEXES, MECHANISM, PROMOTER, NEURONS, Amyloid Precursor Protein Secretases, Aspartic Acid Endopeptidases, Chlorocebus aethiops, HeLa Cells, 0601 Biochemistry and Cell Biology, Developmental Biology, 3101 Biochemistry and cell biology

Abstract:

gamma-Secretase-dependent regulated intramembrane proteolysis of amyloid precursor protein (APP) releases the APP intracellular domain (AICD). The question of whether this domain, like the Notch intracellular domain, is involved in nuclear signalling is highly controversial. Although some reports suggest that AICD regulates the expression of KAI1, glycogen synthase kinase-3beta, Neprilysin and APP, we found no consistent effects of gamma-secretase inhibitors or of genetic deficiencies in the gamma-secretase complex or the APP family on the expression levels of these genes in cells and tissues. Finally, we demonstrate that Fe65, an important AICD-binding protein, transactivates a wide variety of different promoters, including the viral simian virus 40 promoter, independent of AICD coexpression. Overall, the four currently proposed target genes are at best indirectly and weakly influenced by APP processing. Therefore, inhibition of APP processing to decrease Abeta generation in Alzheimer's disease will not interfere significantly with the function of these genes.